Abstract
G-protein-coupled receptors sense extracellular chemical or physical stimuli and transmit these signals to distinct trimeric G-proteins. Activated Gα-proteins route signals to interconnected effector cascades, thus regulating thresholds, amplitudes and durations of signalling. Gαs- or Gαi-coupled receptor cascades are mechanistically conserved and mediate many sensory processes, including synaptic transmission, cell proliferation and chemotaxis. Here we show that a central, conserved component of Gαs-coupled receptor cascades, the regulatory subunit type-II (RII) of protein kinase A undergoes adenosine 3'-5'-cyclic monophosphate (cAMP)-dependent binding to Gαi. Stimulation of a mammalian Gαi-coupled receptor and concomitant cAMP-RII binding to Gαi, augments the sensitivity, amplitude and duration of Gαi:βγ activity and downstream mitogen-activated protein kinase signalling, independent of protein kinase A kinase activity. The mechanism is conserved in budding yeast, causing nutrient-dependent modulation of a pheromone response. These findings suggest a direct mechanism by which coincident activation of Gαs-coupled receptors controls the precision of adaptive responses of activated Gαi-coupled receptor cascades.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptation, Physiological / genetics*
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Cloning, Molecular
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Cyclic AMP / metabolism
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Cyclic AMP-Dependent Protein Kinase Type II / genetics
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Cyclic AMP-Dependent Protein Kinase Type II / metabolism*
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Escherichia coli
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GTP-Binding Protein alpha Subunits / genetics
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GTP-Binding Protein alpha Subunits / metabolism
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Gene Expression Regulation, Fungal / physiology*
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mutation
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Phosphorylation
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Plasmids
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Protein Binding
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Protein Subunits / genetics
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Protein Subunits / metabolism
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism*
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism*
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Signal Transduction / physiology*
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Transformation, Bacterial
Substances
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GTP-Binding Protein alpha Subunits
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Protein Subunits
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Receptors, G-Protein-Coupled
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Recombinant Fusion Proteins
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Saccharomyces cerevisiae Proteins
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Cyclic AMP
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Cyclic AMP-Dependent Protein Kinase Type II
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Mitogen-Activated Protein Kinase 1